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  • Ovid Technologies (Wolters Kluwer Health)  (3)
  • Shendure, Jay  (3)
  • 1
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    Exome Sequencing Identifies SMAD3 Mutations as a Cause of Familial Thoracic Aortic Aneurysm and Dissection With Intracranial and Other Arterial Aneurysms
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Research Vol. 109, No. 6 ( 2011-09-02), p. 680-686
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 109, No. 6 ( 2011-09-02), p. 680-686
    Abstract: Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner. Objective: To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants. Methods and Results: A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G 〉 A), p.E239K (c.715G 〉 A), and p.A112V (c.235C 〉 T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers. Conclusions: SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.111.248161
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1467838-X
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  • 2
    Online Resource
    Online Resource
    LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Research Vol. 118, No. 6 ( 2016-03-18), p. 928-934
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. 6 ( 2016-03-18), p. 928-934
    Abstract: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families. Objectives: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections. Methods and Results: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G 〉 T (p.Ser280Arg), was identified in LOX , encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G 〉 A (p.Trp42*), c.604G 〉 T (p.Gly202*), c.743C 〉 T (p.Thr248Ile), c.800A 〉 C (p.Gln267Pro), and c.1044T 〉 A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections. Conclusions: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.115.307130
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    RNF213 Rare Variants in an Ethnically Diverse Population With Moyamoya Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. 11 ( 2014-11), p. 3200-3207
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 11 ( 2014-11), p. 3200-3207
    Abstract: Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene ( RNF213 ), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States. Methods— We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families. Results— RNF213 p.R4810K was identified in 56% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant. Conclusions— These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.114.006244
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467823-8
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